Tuberculosis is the leading cause of death due to infection, causing an estimated 2.5 million deaths and 7.5 million cases per year worldwide (1). In the United States, rates of tuberculosis began to increase in 1985 after 40 years of steady decline. In addition, a number of American cities are reporting high rates of infection by multiply drug resistant tuberculosis. Such mycobacteria cause a high mortality rate because available antibiotics are ineffective (2).
About 90% of individuals who become infected with M. tuberculosis do not have immediate symptoms but develop a positive reaction to the tuberculin skin test and carry the bacteria in a dormant or latent state (3). Over a lifetime, these individuals have a 10% risk of developing reactivation tuberculosis in which, after years of quiescence, the tubercle bacilli resume growth and cause classic pulmonary tuberculosis as well as other forms of disease. One billion people, roughly one-third of the world's population, have latent tuberculosis (4). Individuals with latent tuberculosis currently require prolonged therapy because antimycobacterial drugs work poorly against dormant bacilli.
Little is known regarding the state of dormant tubercle bacilli within the human host (5). There is a controversial body of literature describing filterable forms, granular bacillary bodies, and L-forms associated with tubercle bacilli (6, 7). These forms were reported as early as 1907 when Hans Much described granular non-acid-fast bacilli in tuberculous abscesses (30). The granules, which came to be known as Much's granules, were filterable, failed to grow in culture, and failed to produce typical tuberculosis when inoculated into animals. However, if tissue from the first animal was inoculated into a second, classic tuberculosis ensued. Similar observations have been reported over the decades for both tuberculosis (31, 32) and leprosy (33, 34). Dormant or altered mycobacterial forms have also been proposed as etiologic agents for granulomatous diseases such as sarcoidosis and inflammatory bowel disease (35). There have been reports of PCR-amplifiable, mycobacterial DNA in the tissues of patients with these diseases (36).
Because latent tubercle bacilli survive for years and cannot be detected by acid-fast staining, the bacilli must be assumed to undergo significant morphologic changes during dormancy. Though these changes are poorly understood, they could involve expression of novel mycobacterial antigens which are not produced or cannot be recovered from bacteriologic cultures grown in vitro.
There is a need in the art for diagnostic and therapeutic methods for detecting, treating, and preventing latent tuberculosis.